tbuckley/cabot-search huggingface dataset:
Abstract 5230: Comprehensive genetic analysis using clinical specimens of gastric adenocarcinoma and proximal polyposis of stomach
Authors: Chihiro Matsumoto, Masaaki Iwatsuki, Koshi Mimori, Hideo Baba
Journal: Cancer Research (2023)

Abstract Background and Purpose: Gastric adenocarcinoma and proximal polyposis (GAPPS) is an autosomal dominant genetic disorder that causes gastric carcinoma from fundus gland polyposis. Although germline mutation of APC promoter 1B was reported as a pathogenic variant in 2016, there are still many unknowns about the carcinogenesis. In this study, we performed a comprehensive Next generation sequencing (NGS) analysis of GAPPS clinical specimens to investigate the molecular profile characteristic of carcinogenesis. Patients and Methods: Seven cases from three GAPPS families experienced in our department were included in this study. In each case, tissues were collected from normal mucosa, polyps, and carcinoma, and FFPE and fresh-frozen samples were prepared. After pathological diagnosis was performed on each sample, RNA and DNA were extracted and analyzed based on data obtained by next generation sequence (NGS). Results: In the RNA sequence, gene expression analysis was performed on 45 pathologically diagnosed samples, which were classified into four clusters by K-means clustering. Gene Set Enrichment Analysis (GSEA) of the four clusters showed that cancer-related genes such as p53 and KRAS were significantly enriched in the cluster of cancer, and genes related to immune response were significantly enriched in the cluster of cancer compared to the and clusters of polyp and normal. Gene mutation analysis using whole-exome sequence (read depth/coverage&amp;gt;20) confirmed mutation of APC promoter 1B in all samples. On the other hand, in tumor samples (N=10), the percentage of mutation of genes previously suggested to be associated with GAPPS (TP53, FBXW7, GNAS, and KRAS) were 50%, 0%, 30%, and 60%, respectively. Conclusion: Comprehensive gene expression analysis by RNA sequence and whole-exome sequence was performed using clinical samples of GAPPS. In the future, we plan to identify specific gene-pathways involved in carcinogenesis. (2460/2600 characters) Citation Format: Chihiro Matsumoto, Masaaki Iwatsuki, Koshi Mimori, Hideo Baba. Comprehensive genetic analysis using clinical specimens of gastric adenocarcinoma and proximal polyposis of stomach. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5230.
Abstract 1464: Exosomal delivery of tumor suppressive microRNA-7 as a novel approach to regulating cervical cancer cell growth
Authors: Gabriella McWilliams, Molly Roy, Daniel Bilbao Cortes, Yu-Ping Yang, Sylvia Daunert, Sapna Deo
Journal: Cancer Research (2023)

Abstract There is an unmet need for more safe, effective, targeted therapy in cervical cancer which this study seeks to meet through the use of exosomes and miRNA. Although cervical cancer is the fourth most prevalent female cancer worldwide, it currently has sparce options for treatment. Early-stage tumors are often surgically removed, while later stage cancers are treated with traditional radiation and chemotherapy methods, which have limited efficacy. Thus, to bridge this gap, we propose the use of exosomes, which are naturally occurring cell-derived vesicles, in combination with microRNA-7 (miR-7), a known tumor-suppressive microRNA, as a potential treatment for cervical cancer. We first transfected adipocyte-derived stem cells (ADSC) with miR-7. ADSC produce exosomes that are immune-compatible, have a long half-life, and have an especially low toxicity, making them a versatile nanocarrier. We collected the conditioned media produced by the ADSC, from which we isolated the miR-7-containing exosomes. The collected exosomes were confirmed to contain the appropriate miRNA by qPCR and applied to HeLa cells, and cellular response and gene expression changes were analyzed via qPCR. Functional assays including proliferation and migration were also performed to analyze the effect of exosome treatment on cell function. Controls for this study included a parallel ADSC transfection with a non-coding, scramble miRNA, as well as HeLa cells treated with exosomes from non-transfected ADSC. Our studies demonstrate that transfection of ADSC with miR-7 produces exosomes with significantly increased levels of this regulatory miRNA, and that these exosomes can specifically deliver their cargo and effectively downregulate the target gene Epidermal Growth Factor Receptor (EGFR), which is involved in tumor progression in cervical cancer. Additionally, we show that these miR-7-containing exosomes decrease proliferation and migration of HeLa cells in our in vitro functional analysis. Ultimately, this technology provides an alternative treatment option that will improve clinical outcomes of women who are affected by cervical cancer. Citation Format: Gabriella McWilliams, Molly Roy, Daniel Bilbao Cortes, Yu-Ping Yang, Sylvia Daunert, Sapna Deo. Exosomal delivery of tumor suppressive microRNA-7 as a novel approach to regulating cervical cancer cell growth [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1464.
Abstract 2629: Single and combined inhibition of PAK and Hippo pathway in NF2-deficient schwannoma
Authors: Dorothy Benton, Jonathan Chernoff
Journal: Cancer Research (2023)

Abstract Neurofibromatosis 2 (NF2) Syndrome is a rare, but devastating genetic condition that leads to non-cancerous tumors of the nervous system. NF2 patients are likely to develop Schwannomas on the eighth cranial nerve that lead to progressive deafness and spinal cord compression as well as meningiomas and peripheral nerve tumors. Effective treatment for these patients is lacking, with risky surgery being the most reliable approach and pharmacotherapies having inadequate results. The hallmark mutation of this condition is inactivation of NF2, which codes for the protein Merlin. Merlin plays several roles in the cell, two of the most consequential being inhibition of PAK1 and activation of the Hippo tumor suppressor pathway. However, drugs targeting these pathways have not yet been investigated in NF2-deficient Schwannoma. In this study, we explored the use of YAP-TEAD inhibitors as well as the combination of Hippo family and Group I PAK inhibition in NF2-deficient Schwannoma cells. We used several Schwannoma cells lines of human, mouse, and rat origin as well as a human Schwann cell line with NF2 knocked out via CRISPR compared to its wild-type control line. We investigated the role of YAP, the main effector of the Hippo pathway, and PAK1/2 in NF2 Schwannoma cells via genetic and pharmacologic inhibition. We also combined YAP-TEAD inhibitors with several PAK family inhibitors to induce a synergistic reduction in cell viability and proliferation as well as an increase in apoptosis. We found that genetic inhibition of both YAP and Group I PAK proteins led to partial reduction in Schwannoma growth. Using several YAP-TEAD binding inhibitors (TED-347, NSC682769, IK-930), Group I PAK inhibitors (FRAX-1036, G555) and PAK1-specific inhibitor (NVS-1-PAK1) we found that YAP-TEAD binding inhibition combined with Group I PAK inhibition has the greatest reduction on Schwannoma cell viability, proliferation, and increase in cell death. Taken together, our findings indicate that both the Hippo pathway and PAK proteins may be viable targets for Schwannoma therapies. Furthermore, combining the two may lead to a synergistic effect and further prevent growth of NF2-deficient Schwannomas. Citation Format: Dorothy Benton, Jonathan Chernoff. Single and combined inhibition of PAK and Hippo pathway in NF2-deficient schwannoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2629.
Abstract 2649: Discovery of a potent, selective, and tumor-suppressing antibody antagonist of DKK1
Authors: Linya Wang, Sean M. Peterson, Ana Lujan, Kara Y. Chan, Cameron F. Hu, Mouna Villalta, Tom Z. Yuan, Zhen Han, Marisa Yang, Vishwas Prabhu, Tammy Htoy, Paul VanDyke, Carson Holliday, Hector Franco, Hansika Wadhwa, Hoa Giang, Ryan Stafford, Fumiko Axelrod, Aaron Sato
Journal: Cancer Research (2023)

Abstract Wnt signaling plays an important role in embryonic development and tumorigenesis. These biological effects are exerted by activation of the β-catenin/TCF transcription complex and consequent regulation of a set of downstream genes. Dickkopf WNT Signaling Pathway Inhibitor 1 (DKK1) has been shown to be a potent inhibitor of Wnt signaling via competing Wnt binding to LRP5/6. DKK1 is tumorigenic in multiple cancer types and also immunosuppressive via MDSCs and NK cells. Emerging evidence indicates that DKK1 has been involved in T cell differentiation and induction of cancer evasion of immune surveillance by accumulating MDSCs. Consequently, DKK1 has become a promising target for cancer immunotherapy, and the mechanisms of DKK1 affecting cancers and immune cells have received great attention. With Twist’s precision DNA writing technologies, we have created phage display libraries with diversity greater than 1 × 1010, and utilized machine learning model for optimal discovery. In this study, we discovered anti-DKK1 antibodies blocking the binding of DKK1 to the receptor. The in vitro functional assays showed that the interaction of Wnt to its receptor was restored in the presence of anti-DKK1 antibodies, resulting in TCF/LEF signaling upregulation. Moreover, anti-DKK1 antibodies induced immune cell activation, and led to tumor cell cytotoxicity. In addition, anti-DKK1 antibodies binding to different domains of DKK1 led to different functional effect. In vivo study indicated anti-DKK1 antibodies is potent in tumor regression. Our anti-DKK1 leads shows promising efficacy in cancer immunotherapy. Citation Format: Linya Wang, Sean M. Peterson, Ana Lujan, Kara Y. Chan, Cameron F. Hu, Mouna Villalta, Tom Z. Yuan, Zhen Han, Marisa Yang, Vishwas Prabhu, Tammy Htoy, Paul VanDyke, Carson Holliday, Hector Franco, Hansika Wadhwa, Hoa Giang, Ryan Stafford, Fumiko Axelrod, Aaron Sato. Discovery of a potent, selective, and tumor-suppressing antibody antagonist of DKK1 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2649.
Abstract 4455: Protein phosphatase 4 inhibition stimulates anti-tumor immunity in ovarian cancer
Authors: Remya Raja, Christopher Wu, Esen Y. Bassoy, Thomas Rubino, Emma Utagawa, Paul Magtibay, Kristina Butler, Marion Curtis
Journal: Cancer Research (2023)

Abstract Background: Increased infiltration of T cells into ovarian tumors has been repeatedly shown to be predictive of enhanced patient survival. However, despite the evidence of an active immune response in OC, immune checkpoint blockade therapy has been ineffective. Recently studies have shown that deficiencies in the DNA damage response (DDR) can drive increased genomic instability and tumor immunogenicity. One target involved in the DDR that has the potential to be of therapeutic value is protein phosphatase 4 (PP4); however, the effect of PP4 deficiency on anti-tumor immunity remain unknown. Results: Our results show that PP4 inhibition combined with carboplatin leads to increased carboplatin sensitivity, DNA damage, and micronuclei formation. Using a panel of ovarian cancer cells, we show that PP4 inhibition triggers inflammatory signaling via NF-κB and STAT1 activation resulting in increased expression of pro-inflammatory cytokines including IFNβ1, CCL5, CXCL10, and IL-6. Moreover, conditioned media from OC cells treated with the combination of PP4 inhibitor and carboplatin significantly increased migration of both CD8 T cell and NK cells over carboplatin treatment alone. Knockdown of STING in OC cells significantly abrogated the increase in CD8 T cell migration induced by PP4 inhibition. PPP4C or PPP4R3B knockdown resulted in strong induction of NK cell IFN-γ, increased degranulation, and increased NK cell-mediated cytotoxicity against OC cells. Stable knockdown of PP4C in a syngeneic, immunocompetent mouse model of ovarian cancer resulted in significant reduction of tumor growth in vivo. PP4C low tumors had increased infiltration of CD161+ NK cells and CD4+ T cells. Addition of low dose carboplatin treatment in vivo led to increased CD8+ T cell infiltration in PP4C low tumors when compared to the untreated groups. Conclusions: Our work has identified a role for PP4 inhibition in promoting anti-tumor immune activation. These findings provide the rationale for combining PP4 inhibitors with immunotherapy as a new approach in ovarian cancer treatment. Citation Format: Remya Raja, Christopher Wu, Esen Y. Bassoy, Thomas Rubino, Emma Utagawa, Paul Magtibay, Kristina Butler, Marion Curtis. Protein phosphatase 4 inhibition stimulates anti-tumor immunity in ovarian cancer. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4455.
Abstract 2620: TRIM4 is the E3 ubiquitin-ligase for TPL2/MAP3K8 and is modulated by oncogenic KRAS
Authors: Sapana Prakashrao Bansod, Paarth B. Dodhiawala, Ashenafi Bulle, Peng Liu, Lin Li, Patrick M. Grierson, Jason Held, Kian-Huat Lim
Journal: Cancer Research (2023)

Abstract TPL2 (tumor progression locus 2, a. k. a. Cot/MAP3K8) kinase becomes oncogenic via disruption of the C-terminus, which abrogates its proteasomal degradation. However, the mechanism underlying degradation of TPL2 remains unclear. Using proximity-dependent biotin identification (BioID), for the first time we have discovered that Tripartite Motif Containing 4 (TRIM4) is the E3-ligase that binds and degrades TPL2 via polyubiquitination of lysine 415 and 439. Notably, naturally-occurring oncogenic R442H and E188K mutations in TPL2 abrogated the binding and polyubiquitination by TRIM4. Furthermore, KRAS oncoprotein stabilizes TPL2 by promoting TRIM4 degradation. Using immunoprecipitation-mass spectrometry, we identified TRIM21 as a ligase that binds and stabilizes TRIM4, in part by reducing TRIM4 polyubiquitination. Therefore, oncogenic KRAS binds to and promotes TRIM21 degradation, destabilizing TRIM4 and prolonging the half-life of TPL2. Overall, we discovered novel mechanisms of TPL2 regulation which are influenced by oncogenic KRAS, providing opportunities for the development of novel therapies. [S. Bansod and P.B. Dodhiawala contributed equally to this work.] Citation Format: Sapana Prakashrao Bansod, Paarth B. Dodhiawala, Ashenafi Bulle, Peng Liu, Lin Li, Patrick M. Grierson, Jason Held, Kian-Huat Lim. TRIM4 is the E3 ubiquitin-ligase for TPL2/MAP3K8 and is modulated by oncogenic KRAS [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2620.
Abstract 1388: Non-thermal plasma-activated medium induces ferroptotic cell death by intracellular ferrous iron overload in head and neck cancer
Authors: QuocKhanh Nguyen, Chan Oh, Seung-Nam Jung, Yudan Piao, Mi Ae Lim, Young Il Kim, Yanli Jin, Hae Jong Kim, Bon Seok Koo
Journal: Cancer Research (2023)

Abstract The notoriously high proliferation rate of cancer cells requires them to constantly deal with the balance adjustment between oxidative stress overload and upregulated protective antioxidant pathways. It puts them in a vulnerable state whenever one piece of this puzzle went out of control. Non-thermal plasma (NTP) is partially ionized gas operated at or around body temperature and has emerged as a new potential anti-cancer therapy due to its ability to release and induce ROS, RNS, and other free radicals as well as generate UV- photon and electromagnetic field; but the specific mechanism and its specificity to cancer cell are still controversial. Using transcriptomic analysis, we previously reported the link between NTP-activated media (NTPAM)and apoptosis; but the sequencing data also revealed a strong Ferroptotic response in all the 6Head and Neck cancer cell lines we checked. Ferroptosis is a newly identified oxidative-regulated cell death, characterized by the iron-dependent generation of lipid peroxidation. In this study, we found the prolonged treatment of NTPAM-induced cell death via the non-canonical ferroptosis pathway by directly increasing intracellular toxic ferrous Iron (Fe2+). We found that the excessive overexpression of HMOX1 under prolonged NTPAM-induced oxidative stress was actually responsible for the surge of intracellular Fe2+ due to the increase of heme degradation. Pharmacological inhibition or RNA silencing of HMOX1 was able to rescue 2 HNC cell lines from NTPAM-induced increased Iron concentration as well as ferroptosis cell death, both in vivo and in vitro. These results suggest NTP directly induces ferroptosis via an increase of Fe2+ concentration by triggering the over-responding of the NRF2 - HMOX1 antioxidant system. This finding could be exploited to develop future NTP-based cancer therapy as well as in combination with other Iron sensitive anti-neoplastic agents; and could be a potential method of overcoming conventional cancer treatment resistance. Citation Format: QuocKhanh Nguyen, Chan Oh, Seung-Nam Jung, Yudan Piao, Mi Ae Lim, Young Il Kim, Yanli Jin, Hae Jong Kim, Bon Seok Koo. Non-thermal plasma-activated medium induces ferroptotic cell death by intracellular ferrous iron overload in head and neck cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1388.
Abstract 263: Automating next generation sequencing workflows for custom hyb panels: high quality library preparation and target enrichment on the Biomek NGeniuS System
Authors: Nicole Roseman, Laura Tucker, Francesco Criscuolo, Lynette Lewis, Li Liu, Tyler Buit, Jasmeen Mandair, Zachary Smith, Calvin Cortes
Journal: Cancer Research (2023)

Abstract This study investigates a custom 2Mb xGen Hyb panel designed against mutated gene targets implicated in several cancers using an end-to-end assay workflow on the Biomek NGeniuS platform. Automation in laboratories is advantageous to generate reproducible next generation sequencing (NGS) sample libraries, however, assay automation differs from instrument vendor to vendor but also from lab to lab with different deck layouts of the same instrument. These differences require a significant amount of optimization to design the workflow and begin generating NGS libraries. In addition to this optimization, some research, e.g., cancer research utilizes low input and/or degraded samples such as cfDNA from plasma or FFPE biopsies. Integrated DNA Technologies (IDT) and Beckman Coulter - Life Sciences together provide a walk away NGS automation solution for these research samples directly upon instrument installation with no optimization required by combining Beckman Coulter’s Biomek NGeniuS with IDT’s xGen cfDNA &amp; FFPE DNA Library Prep kit and xGen Hybridization Capture. This trio provides a solution for laboratories to minimize technician hands-on time, error reduction, and rework while improving flexibility. IDT’s xGen cfDNA &amp; FFPE DNA Library Prep kit utilizes novel chemistry to maximize sample input conversion, suppress adapter-dimer formation, and facilitate consensus analysis. IDT’s xGen Hybridization Capture products maintain high library diversity, obtain high on-target, and provide consistent and uniform sequencing coverage regardless of panel size. We demonstrate performance of this complete workflow with a custom 2Mb xGen Hyb panel yielding high library complexity, high on-target coverage, and capture uniformity. The combination of IDT’s xGen library preparation solutions on the NGeniuS Biomek platform provides a reliable and consistent solution that can be instantly downloaded from the portal straight to analysis of precious low input and degraded samples. Citation Format: Nicole Roseman, Laura Tucker, Francesco Criscuolo, Lynette Lewis, Li Liu, Tyler Buit, Jasmeen Mandair, Zachary Smith, Calvin Cortes. Automating next generation sequencing workflows for custom hyb panels: high quality library preparation and target enrichment on the Biomek NGeniuS System [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 263.
Abstract 6249: Low Bcl-2 is a robust biomarker of sensitivity to nab-paclitaxel in Ewing sarcoma
Authors: Guillem Pascual-Pasto, Claudia Resa-Pares, Angel M. Carcaboso
Journal: Cancer Research (2023)

Abstract Nanoparticle albumin-bound paclitaxel (nab-paclitaxel) shows potent preclinical anticancer activity in pediatric solid tumors such as Ewing sarcoma, rhabdomyosarcoma and neuroblastoma, but responses in clinical trials have been modest. In this work, we aimed to discover a rational biomarker-based approach to select the right candidate patients for this treatment. We assessed the efficacy of nab-paclitaxel in 27 patient-derived xenografts (PDX), including 14 Ewing sarcomas, five rhabdomyosarcomas and several other pediatric solid tumors. Response rate (partial or complete response) was remarkable in rhabdomyosarcomas (four of five) and Ewing sarcomas (four of 14). We addressed several predictive factors of response to nab-paclitaxel such as the expression of the secreted protein acidic and rich in cysteine (SPARC), chromosomal stability of cancer cells and expression of antiapoptotic members of the B-cell lymphoma-2 (Bcl-2) family of proteins such as Bcl-2, Bcl-xL, Bcl-W and Mcl-1. Protein (immunoblotting) and gene expression of SPARC correlated positively, while immunoblotting and immunohistochemistry expression of Bcl-2 correlated negatively with the efficacy of nab-paclitaxel in Ewing sarcoma PDX. The negative correlation of Bcl-2 immunoblotting signal and activity was especially robust (r = 0.8352; P = 0.0007; Pearson correlation). Consequently, we evaluated pharmacological strategies to inhibit Bcl-2 during nab-paclitaxel treatment. We observed that the Bcl-2 inhibitor venetoclax improved the activity of nab-paclitaxel in highly resistant Bcl-2-expressing Ewing sarcoma PDX. Overall, our results suggest that low Bcl-2 expression could be used to select patients with Ewing sarcoma sensitive to nab-paclitaxel, and Bcl-2 inhibitors could improve the activity of this drug in Bcl-2-expressing Ewing sarcoma. Citation Format: Guillem Pascual-Pasto, Claudia Resa-Pares, Angel M. Carcaboso. Low Bcl-2 is a robust biomarker of sensitivity to nab-paclitaxel in Ewing sarcoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 6249.